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Published on: July 17, 2019
ABL1/2 and DDR1 Drive MEKi Resistance in NRAS-Mutant Melanomas by Stabilizing RAF/MYC/ETS1 and Promoting RAF
Anastasia Lyon1, Rakshamani Tripathi1, Christina Meeks1
1Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
Abstract:
Melanomas harboring NRAS mutations are a particularly aggressive and deadly subtype. If patients cannot tolerate or the melanomas are insensitive to immune checkpoint blockade, there are no effective 2nd-line treatment options. Drugs targeting the RAF/MEK/ERK pathway, which are used for BRAF-mutant melanomas, do little to increase progression-free survival (PFS). Here, using both loss-of-function and gain-of-function approaches, we show that ABL1/2 and DDR1 are critical nodes during NRAS-mutant melanoma intrinsic and acquired MEK inhibitor (MEKi) resistance. In some acquired resistance cells, ABL1/2 and DDR1 cooperate to stabilize RAF proteins, activate ERK cytoplasmic and nuclear signaling, repress p27/KIP1 expression, and drive RAF homodimerization. In contrast, other acquired resistance cells depend solely on ABL1/2 for their survival, and are sensitive to highly specific allosteric ABL1/2 inhibitors, which prevent β-catenin nuclear localization and destabilize MYC and ETS1 in an ERK-independent manner. Significantly, targeting ABL1/2 and DDR1 with an FDA-approved anti-leukemic drug, reverses intrinsic MEKi resistance, delays acquisition of acquired resistance, and doubles the survival time in a NRAS-mutant mouse model. These data indicate that repurposing FDA-approved drugs targeting ABL1/2 and DDR1 may be a novel and effective strategy for treating patients with treatment-refractory NRAS-driven melanomas.
Insights
Targeting ABL1/2 and DDR1 with FDA-approved drugs overcomes MEK inhibitor resistance in NRAS-mutant melanoma. This strategy doubles survival in mouse models, offering a new treatment for refractory melanomas.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- NRAS-mutant melanomas are aggressive with limited treatment options after immune checkpoint blockade failure.
- Current MEK inhibitors (MEKi) show limited efficacy in NRAS-mutant melanoma, especially upon acquired resistance.
Purpose of the Study:
- To identify critical molecular targets driving intrinsic and acquired MEK inhibitor resistance in NRAS-mutant melanoma.
- To evaluate the therapeutic potential of targeting identified nodes, including repurposing FDA-approved drugs.
Main Methods:
- Utilized loss-of-function and gain-of-function genetic approaches to investigate NRAS-mutant melanoma resistance mechanisms.
- Employed an FDA-approved anti-leukemic drug targeting ABL1/2 and DDR1 in preclinical models.
Main Results:
- Identified ABL1/2 and DDR1 as key regulators of MEK inhibitor resistance in NRAS-mutant melanoma.
- Demonstrated that ABL1/2 and DDR1 cooperate to stabilize RAF proteins and activate ERK signaling in some resistant cells.
- Showed that targeting ABL1/2 with specific inhibitors can overcome resistance independently of ERK signaling.
- Repurposing an FDA-approved drug targeting ABL1/2 and DDR1 reversed intrinsic resistance, delayed acquired resistance, and doubled survival in a mouse model.
Conclusions:
- ABL1/2 and DDR1 are critical therapeutic targets for overcoming MEK inhibitor resistance in NRAS-mutant melanoma.
- Repurposing FDA-approved drugs targeting ABL1/2 and DDR1 presents a promising novel strategy for treatment-refractory NRAS-driven melanomas.
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